The present program project has the overall goal of elucidating the mechanism(s) underlying cognitive decline with aging. To achieve this goal, we have organized a program of research that includes 4 research projects, three essential core facilities and a group of talented investigators. The research program is driven by the now strongly supported hypothesis that oxidative stress in the brain leads to age-related oxidative damage and is a major determinant of the rate of cognitive aging. An essential approach to this problem is to define the animal-to-animal variability in cognitive aging, relate these inter-animal differences to oxidative damage in specific brain regions and to determine the signaling pathways that communicate oxidative events to cellular responses. As such, the four research projects focus on a systematic assessment of these issues. Project 1 will define the rate and inter-animal differences in cognitive and psychomotor aging in C57BL/6 mice and define the relationship between these behaviors and regional, cellular, subcellular and molecular oxidative damage in the brain as well as the ability of caloric restriction to affect these events. Project 2 will determine the mechanism by which estrogens attenuate the activation of NFKB, a major oxidative signaling pathway, and thereby reduce neuronal vulnerability during aging. Project 3 will determine the effects of cognitive aging and oxidative stress on intracellular Ca 2+ channels, their associated signaling proteins and the resulting effects on intracellular Ca 2+ homeostasis. Project 4 will assess the other important ovarian steroid, progesterone, for its effects on cognitive aging and brain health, based upon preliminary data that indicate that progesterone is a potent inhibitor of the GABAA receptor and a potent neuroprotectant. All of these research projects are interactive in the sharing of ideas, tissues, and the use of behaviorally characterized mice that are distributed to projects based upon their presentation of the behavioral diversity of the population as a whole. This is achieved through an Administrative Core (Core A) that will oversee the program, a Animal Care Behavioral and Assessment Core (Core B) that will provide care for and behavioral characterization of all mice and a Biostatistics Core (Core C) that will provide statistical design, animal randomization and analysis of all data generated. This statistically based, multidisciplinary program of research, aimed at the characterization of cognitive aging, will enhance our understanding of the role of oxidative stress in cognitive aging, the mechanisms mediating these effects and potential targets for effective intervention.